Title: MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage.
Authors: Huang, Jen-Wei; Acharya, Ananya; Taglialatela, Angelo; Nambiar, Tarun S; Cuella-Martin, Raquel; Leuzzi, Giuseppe; Hayward, Samuel B; Joseph, Sarah A; Brunette, Gregory J; Anand, Roopesh; Soni, Rajesh K; Clark, Nathan L; Bernstein, Kara A; Cejka, Petr; Ciccia, Alberto
Published In Nat Commun, (2020 06 11)
Abstract: Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. Here we characterize C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a DNA repair factor involved in HR. MCM8IP-deficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition. Importantly, we report that MCM8IP directly associates with MCM8-9, a helicase complex mutated in primary ovarian insufficiency, and RPA1. We additionally show that the interactions of MCM8IP with MCM8-9 and RPA facilitate HR and promote replication fork progression and cellular viability in response to treatment with crosslinking agents. Mechanistically, MCM8IP stimulates the helicase activity of MCM8-9. Collectively, our work identifies MCM8IP as a key regulator of MCM8-9-dependent DNA synthesis during DNA recombination and replication.
PubMed ID: 32528060
MeSH Terms: Cell Line, Tumor; Cell Survival/genetics; Chromatin/genetics; Chromatin/metabolism; DNA Damage*; DNA Replication*; DNA, Single-Stranded/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism*; HCT116 Cells; HEK293 Cells; Humans; Minichromosome Maintenance Proteins/genetics; Minichromosome Maintenance Proteins/metabolism*; Mutation; Protein Binding; Rad51 Recombinase/metabolism; Recombinational DNA Repair*; Replication Protein A/genetics; Replication Protein A/metabolism